Controlling Pain in Liver Biopsy, or "We Will Probably Need to
Repeat the Biopsy in a Year or Two to Assess the Response"

Stephen H. Caldwell, M.D

Liver biopsy is a fundamentally important procedure in the evaluation
of chronic and acute liver diseases. Although specific figures are not
available, the epidemic of hepatitis C, the growing number of therapeutic
options in various liver diseases, and, more recently, the recognition
of the potential severity of fatty liver have increased the number of
biopsies in most centers over the past 10 yr. Based on the experience
at our center, where approximately five biopsies are performed per week,
it can be conservatively estimated that over 30,000 liver biopsies are
performed annually in the US (assuming an average of three similar centers
per state). Surrogate markers for measuring the degree of liver injury
continue to attract attention but are unlikely to supplant histological
examination in the foreseeable future (1).
Because of the central role of liver biopsy in diagnosis, staging, and
assessing treatment response, it is important to examine ways to make
the procedure more acceptable to patients. Castéra et al.
have addressed this problem in an article in this issue (2)
reporting on a placebo-controlled trial of self-administered nitrous oxide
in patients undergoing percutaneous liver biopsy.

Postbiopsy pain is the most common complication of liver biopsy, although
the incidence varies depending on the assessment of severity (3).
Moderate to severe pain, often requiring hospitalization, is seen in 1-5%
of patients in past series (4, 5).
Aside from trauma to adjacent organs, the pain in this situation is more
often associated with the need for blood transfusions and hence is likely
related to frank bleeding, although most recover with only supportive
measures. The higher range is seen with cutting needles (6)
(such as Tru-Cut [Travenol, Deerfield, IL]) as opposed to aspiration needles
[such as Menghini style (7) needles],
although this is disputed (5). Similarly,
the amount of moderate to severe pain experienced by the patient varies
with the experience of the practitioner (8),
although there is also disagreement on this point (5).

The incidence of less severe pain has been reported in several studies.
Pain requiring postprocedure analgesia is seen in approximately 50% of
patients undergoing biopsy with an automated cutting needle, but this
figure is reduced to approximately 30% when ultrasound is used to guide
the cutting needle (9). In contrast, in
a series of 101 consecutive patients undergoing non-ultrasound
guided biopsy with an aspiration needle (1.6 mm, Jamshidi, Allegiance,
McGaw Park, IL), 34% of the patients experienced pain requiring analgesics
(10). In this issue's Castéra
et al. study, which also used an aspiration needle (1.8 mm, Hepafix,
Braun, Melsungen, Germany), 39% of patients in the placebo group reported
postprocedure pain. Thus, the overall frequency of pain requiring analgesics
appears to be around 30-50% in patients not receiving prebiopsy medications.
It is worth noting that moderate pain was reported in about 30-40% of
patients using the non-ultrasound guided aspiration needles (Menghini
style, such as Jamshidi or Hepafix) in two studies. A similar figure for
the cutting needle was obtained only with ultrasound guidance.
It is speculative, but this difference may relate to the loss of tactile
guidance with the automated cutting needles relative to the aspiration
needles and perhaps the longer dwell-time of the latter needle style (11).

Outside of frank trauma to adjacent organs or severe bleeding, the mechanism
of postbiopsy pain is uncertain. Small hematoma formation has been implicated
in one study that reported that 20% of liver biopsy patients had postbiopsy
hematomas (12). However, these findings
were disputed in a number of letters written in response to that report
(13, 14,
15). On the other hand, surface bleeding
at the biopsy site is almost universal, as any laparoscopist will attest.
Oozing typically commences immediately when the needle is withdrawn and
sometimes begins with a slight gush. Liver bleeding timethe time
until the oozing spontaneously stopsis typically 3-5 min (16).
The amount of blood is usually only 30-50 ml as estimated by gross inspection.
However, it seems likely that this hemodynamically inconsequential amount
of blood is the source of most postbiopsy pain because of irritation of
the capsule and peritoneum. This relationship is supported by the low
frequency of pain (10%) reported in a study of percutaneous biopsy site
plugging (17) and the significantly decreased
liver bleeding time noted laparoscopically when plugging agents are used
(18).

Castéra and colleagues report a novel, convenient, inexpensive
means of controlling pain in patients undergoing standard percutaneous
liver biopsy. One hundred average risk patients undergoing percutaneous
biopsy with an aspiration style needle (1.8 mm, Hepafix) with local xylocaine
were randomized to either a mixture of equal parts N2O/oxygen
or an oxygen placebo. The study was blinded and pain was measured by a
previously reported visual analog pain score in which the patient made
a mark on a 10-mm line to indicate no pain (at the far left of the line)
or maximal pain (at the far right). The gas was delivered via face mask
by a self-activated device that required triggering by the patient to
activate. When drowsiness developed, the patient relaxed the grip on the
mask and thus turned off gas flow. Using this device, the authors noted
a significant decrease in the mean reported pain scores and a complete
absence of pain in 19 patients (38%) in the treatment group versus
only two (4%) in the placebo group. One patient (2%) in the treatment
group experienced severe pain, compared to nine (18%) in the placebo group.
A nurse, trained in use of the dispenser, supervised the administration
of the nitrous oxide, which cost an estimated $4/patient. Their results
offer potential benefit in pain relief, as compared with results using
either an aspiration or a cutting needle in nonpremedicated patients.

In the US, the performance of percutaneous liver biopsy has undergone
remarkable changes recently. Although biopsy remains a staple in most
academic GI/hepatology units, the procedure appears to be performed less
commonly by gastroenterologists in private practice. We recently polled
16 of our past fellows who are now in private practice. Only one-half
continued to perform liver biopsy on a routine basis, and one-half did
not perform the procedure at all. Relatively poor reimbursement in proportion
to liability for a high risk procedure was cited as a major reason for
not performing biopsy. Although abundant historical and more recent literature
support the use of traditional percussion-guided biopsy (19,
20), heightened worry over liability
using this method as opposed to ultrasound-guided biopsy has added to
a shift toward performance of biopsy in the radiology suite. This carries
with it a move toward more frequent use of automated cutting needles and
a rate of postprocedure pain similar to that seen with percussion-guided
aspiration needles (around 30% requiring postprocedure analgesia).

Although the risk of a serious problem is low, the possibility of a severe
adverse event and the uncertainty of interpreting postprocedure pain can
cause a great deal of angst. In comparison to the utility of the procedure
in liver disease and the seriousness with which one must approach liver
biopsy, the typical reimbursement seems remarkably casual. The relative
value unit for standard liver biopsy was 3.43 last year (Current Procedural
Terminology code 47000). In our area, this translates to a Medicare allowable
reimbursement of $106 for the professional fee. For a procedure with potentially
severe complications, this amounts to an inadequate reimbursement for
many practitioners facing tight schedules and decreased reimbursements
in other areas. Some gastroenterologists have adapted to this climate
by incorporating ultrasound guidance into their own practice, although
the Medicare allowable for guidance is a modest $34 in our region, whereas
Blue Shield allows $45. In comparison, the Medicare allowable for a skin
biopsy is $41.40 and that for percutaneous kidney biopsy is $160 in our
region (not calculated with ultrasound guidance).

Is use of nitrous oxide likely to be adopted in endoscopy or radiology
units performing liver biopsy? Castéra et al. have demonstrated
the efficacy of their nitrous oxide system in controlling pain after routine
percutaneous biopsy in this randomized, placebo-controlled trial (2).
However, adoption of the system poses several problems. First, as pointed
out by the authors, the system costs about $700 to set up (including the
delivery apparatus with valves and mask). In addition, there are concerns
about possible exposure to personnel administering the agent. Moreover,
nurse training would be required to safely use this form of analgesia.
Nursing supervision of conscious sedation is standard in most endoscopy
units but requires additional arrangements in many radiology suites where
sedation and analgesic use has not been standard practice. Adoption of
this technique is furthermore unlikely to avoid the need for an i.v.
line placed as a safety measure in case of a complication. In addition,
many practitioners have already adopted routine use of premedications
before the biopsy.

Thus, there are a number of obstacles that make widespread adoption of
this system unlikely in the US. On the other hand, the authors have highlighted
the need for attention to patient comfort in this increasingly common
procedure, and they have provided evidence supporting a valid means of
substantially achieving this goal. Their findings should be borne in mind
the next time one finds oneself discussing liver biopsy with a patient
and the potential need for repeating the biopsy at some point in the future.
It is unclear whether or not similar results in pain control could be
obtained with more routine use of prebiopsy i.v. sedation or small
doses of i.v. analgesics. However, use of a self-activated nitrous
oxide analgesic system would likely be welcome by most patients and appears
to offer effective analgesia at a low price per patient and with a quick
recovery.

Acknowledgments

The author thanks Ms. Greta Hedberg for her assistance in obtaining reimbursement
information.

Division of Gastroenterology and Hepatology, Department
of Internal Medicine, University of Virginia, Charlottesville, Virginia